Acute lymphocytic leukemia (ALL) is the most common cancer of childhood. This disease is caused by developmental arrest and clonal expansion of a transformed, immature lymphocyte. Until recently all leukemias carried a poor prognosis. What sets ALL apart from other leukemias such as acute and chronic myeloid leukemias (AML and CML) is the fact that, with rare exceptions, a leukemic stem cell in ALL has so far not been convincingly demonstrated. The stem cell characteristics of the malignantly transformed cell underlying CML make this disease a treatment challenge because complete eradication of the leukemic stem cell would entail destruction of all hematopoietic stem cells. This may explain why great strides have been made in the treatment of ALL with multi-agent chemotherapy alone, while (with rare exceptions, e.g., M3 AML) that is not the case for AML and CML, where bone marrow transplantation is superior to chemotherapy alone (Nesbit et al., J Clin Oncol 12:127-135, 1994; Clift and Storb. Bone Marrow Transplant 17 Suppl 3:S1-3, 1996). However, ALL treatment comes at a high price in the form of severe side effects, especially so in the case of T-cell acute lymphocytic leukemia (T-ALL), which is the most difficult form of childhood ALL to treat (Goldberg et al., J Clin Oncol 21:3616-3622, 2003).
The reason why side effects from conventional chemotherapy are so common is based on the mechanism of action of most chemotherapeutic agents: they interfere with various phases of the cell cycle (Oeffinger et al., N Engl J Med 355:1572-1582, 2006). Therapeutic benefit comes from the fact that leukemic cells cycle much faster than cells from other body tissues, so that the former are predominantly affected. However, any cell in the body that divides during chemotherapy will also be affected, which leads to short term (hair loss, vomiting) and long term (weakening of bones, short stature, infertility, learning deficits, heart disease and secondary cancers) side effects. Therefore, the future of successful leukemia treatment lies in more targeted therapy that affects only leukemic cells (or the lineage they are derived from) to reduce toxic side effects. Several strategies have been employed to this effect.
For Philadelphia chromosome (t9;22) positive CML, a specific inhibitor, Gleevec, of the BCR/ABL tyrosine kinase was developed (Druker et al., Nat Med 2:561-566, 1996). While not curative, Gleevec has been successfully applied in clinical practice (Druker et al., N Engl J Med 355:2408-2417, 2006) to induce prolonged remissions, and is well tolerated. In AML, the success of the differentiation-inducing effect of all trans retinoic acid (ATRA) in the treatment of M3 AML has led to the search for FDA approved drugs that induce differentiation of AML cell lines (Randolph, Clin Lab Sci 13:106-116, 2000; Randolph, Clin Lab Sci 13:98-105, 2000). This resulted in the identification of compounds such as iressa (Stegmaier et al., Blood 106:2841-2848, 2005)—not previously known or suspected to have anti-AML activity—that can now be tested for efficacy in the treatment of AML.
Recent research in T-ALL revealed a surprisingly high number of cases where Notch-1 is deregulated (reviewed in Grabher et al., Nat Rev Cancer 6:347-359, 2006; Weng et al., Science 306:269-271, 2004), a pathway that also includes c-myc activation (Weng et al., Genes Dev 20:2096-2109, 2006). This has led to first attempts to treat patients with Notch-1 deregulated T-ALL with gamma secretase inhibitors (reviewed in (Aster, Int J Hematol 82:295-301, 2005). While roughly half of T-ALL patients appear have Notch-1 pathway deregulation, others have defective wnt-signaling (Guo et al., Blood in-press, 2007) or other, unknown genetic aberrations that lead to leukemogenesis.
When the molecular target, such as a deregulated proto-oncogene, is unknown, an alternative approach comprises the ablation of the entire hematopoietic lineage that the transformed leukemic cell is derived from. This approach is best exemplified by the use of the anti-CD20 monoclonal antibody Rituximab. In non-Hodgkin lymphoma, expression of the surface marker CD20 has been exploited successfully for elimination of lymphoma cells along with almost all B cells using Rituximab (Cvetkovic Perry. Drugs 66:791-820, 2006). Rituximab is also effective in treating non-malignant, autoimmune hematologic diseases (Bennett et al., Blood 107:2639-2642, 2006; Heidel et al., Thromb Haemost 97:228-233, 2007). Downsides of antibody treatments are side effects and high cost.
An additional treatment alternative is the use of small chemical molecules that are capable of eliminating a subset of hematopoietic cells. Small molecule activity can be detected in assays for functional inhibition of a particular molecular target (e.g., Gleevec against kinase activity of BCR/ABL), or in screens that interrogate a particular pathway or developmental process. The latter approach is particularly powerful if molecular targets affected in a disease or developmental process is unknown (Peterson et al., Proc Natl Acad Sci USA 97:12965-12969, 2000).
What are needed in the art are new T-cell specific drugs that can improve efficacy of treatment and reduce side effects from treatment in patients with T-cell mediated diseases like T-ALL. As the molecular target in a large number of patients with T-ALL has not been identified, an unbiased, novel approach to the therapy of this disease is needed. As such, a small molecule library of compounds has been screened in live, transgenic zebrafish and in vitro against human T-ALL cell lines. These compounds, including derivatives and pharmaceutical salts thereof, are disclosed herein, as are methods of making and using such compositions.